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Identifying patients eligible for PARP inhibitor treatment: from NGS-based tests to 3D functional assays

British Journal of Cancer volume 125, pages 7–14 (2021)Cite this article

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Abstract

Within the past few years, poly (ADP-ribose) polymerase inhibitors (PARPi) have been added to the standard of care for cancer patients, mainly for those exhibiting specific genomic alterations in the homologous recombination (HR) pathway. Until now, patients who are eligible to receive PARPi have been identified using next-generation sequencing (NGS) of gene panels. However, NGS analyses do have some limitations, with a subset of patients with negative NGS-based results can exhibit a clinical benefit, responding positively to PARPi, despite the failure to detect dynamic and predictive biomarkers such as mutated BRCA1/2 genes. Furthermore, the sequencing of initial tumour does not allow to detect reversions or secondary mutations that can restore proficient HR and lead to PARPi resistance. Therefore, it is crucial to better identify patients who are likely to benefit from PARPi treatment. In this context, tumour models such as patient-derived xenografts or tumour-derived organoids could help to guide clinicians in their decision making as these models accurately mimic phenotypic and genetic tumour heterogeneity, and could reflect treatment response in an integrative manner. In this Perspective article, we provide an overview of the currently available NGS-based tests that enable the identification of patients who might benefit from PARPi, and outline breakthroughs and discoveries to expand this selection using 3D functional assays. Combining NGS with functional assays could facilitate the efficient identification of patients, thereby improving patient survival.

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Fig. 1: Next-generation sequencing workflow based on hybrid capture.
Fig. 2: Detection of gene impairments using companion diagnostic (CDx) tests.
Fig. 3: A proposed integrative approach to assess PARPi sensitivity.

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Authors and Affiliations

  1. Normandie University, UNICAEN, INSERM U1086 ANTICIPE (Interdisciplinary Research Unit for Cancers Prevention and Treatment), BioTICLA Team (Biology and Innovative Therapeutics for Ovarian Cancers), Caen, France

    Pierre-Marie Morice, Elodie Coquan, Louis-Bastien Weiswald, Bernard Lambert & Laurent Poulain

  2. UNICANCER, Comprehensive Cancer Center François Baclesse, Caen, France

    Pierre-Marie Morice, Elodie Coquan, Louis-Bastien Weiswald, Bernard Lambert & Laurent Poulain

  3. UNICANCER, Department of Medical Oncology, Comprehensive Cancer Center François Baclesse, Caen, France

    Elodie Coquan

  4. UNICANCER, Department of Clinical Research, Comprehensive Cancer Center François Baclesse, Caen, France

    Elodie Coquan

  5. Normandie University, UNICAEN, INSERM U1086 ANTICIPE, ORGAPRED Platform, Caen, France

    Louis-Bastien Weiswald & Laurent Poulain

  6. UNICANCER, Department of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen, France

    Dominique Vaur

  7. Normandy University, UNIROUEN, INSERM, U1245, Normandy Center for Genomic and Personalized Medicine, Rouen, Caen, France

    Dominique Vaur

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Conception and design: P.-M.M., L.P. Methodology: NA. Acquisition of data and writing: all authors. Administrative, technical, or material support: NA. Study supervision: P.-M.M., L.P.

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Correspondence to Laurent Poulain.

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P.-M.M. was supported by the Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019 (doctoral grant) and from the Comprehensive Cancer Center F. Baclesse. P.-M.M., L.-B.W., B.L. and L.P. are members of the “Réseau Normand d’Innovation Thérapeutique en Oncologie (ONCOTHERA)” network. “ONCOTHERA” European project is co-funded by the Normandy County Council and the European Union within the framework of the Operational Program ERDF/ESF 2014-2020. Work of the laboratory on ovarian cancer organoids is supported by Cancéropôle Nord-Ouest (“ORGRAFT” project), Ligue contre le Cancer (Calvados’s commitee), Fondation de l’Avenir (#AP-RM-19-020), the “Fondation ARC pour la recherche sur le cancer” (#PJA20191209649), and by the Normandy County Council and the European Union within the framework of the Operational Program ERDF/ESF 2014-2020 (“ORGATHEREX” and “ORGAPRED” projects).

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Morice, PM., Coquan, E., Weiswald, LB. et al. Identifying patients eligible for PARP inhibitor treatment: from NGS-based tests to 3D functional assays. Br J Cancer 125, 7–14 (2021). https://doi.org/10.1038/s41416-021-01295-z

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